1. Field of the Invention
The present invention relates to a process for the production of a 3-hydrocarbyl-3-cephem derivative by providing a 3-triflyloxy-3-cephem intermediate, reacting the intermediate with a 1-alkenyltributylstannane in the presence of bis(dibenzylideneacetonyl)-palladium and a phosphine and a metal halide. The resulting 3-unsaturated alkyl-3-cephems are useful as broad spectrum antibacterial agents.
2. Background Art
Hoshi et al., U.S. Pat. Nos. 4,591,641 (5/86) and 4,520,022 (5/85), both of which are owned by the assignee of the present invention, disclose vinyl-substituted cephalosporins having the 3-((Z)-1-propenyl) and 7-phenylglycylamido groups represented by the structural formula, A, ##STR1##
wherein the 3-propenyl group has the (Z) configuration. These patented compounds were produced by forming a substituted vinyl group in the 3-position of the cephalosporin nucleus by reacting a 3-halomethyl cephalosporin or an alkyl halide (e.g., methyl halide) with a triarylphosphine to yield a phophoranyl intermediate which is then treated with a alkylhydrogencarbonyl reagent or a 3-hydrogencarbonyl cephalosporin, respectively. The foregoing compounds were produced by application of the synthetic routes disclosed in U.S. Pat. Nos. 3,769,277 (10/73), 3,994,884 (11/76), and 4,107,431 (8/78).
Long et al., U.S. Pat. No. 3,769,277 (10/73)disclose .DELTA..sup.3 -4-carboxy cephalosporins of the formula ##STR2## by reacting a 3-formyl (i.e. a 3-hydrogencarbonyl)cephalosporin with a phosphorane of the formula R3P=CR3R4
Weir, U.S. Pat. No. 3,994,884 (11/76) discloses the preparation of -66 .sup.3 -4-carboxy cephalosporin having a 3-vinyl group by reacting the corresponding 3-halomethyl cephalosporin compound with a phosphine to obtain the phosphonium intermediate, converting the phosphonium intermediate to the corresponding phosphoranylidene intermediate, and coupling the phosphoranylidene intermediate with formaldehyde.
Clark, et al., U.S. Pat. No. 4,107,431 (8/78) (GB No. 1342241), disclose the preparation of .DELTA. .sup.3 -vinyl or substituted vinyl-4-carboxy cephalosporins by reacting a 3-phosphoranylidene cephalosporin with a carbonyl compound of the formula R3COR4 or by reacting a 3-formyl cephalosporin with a phosphorane of the formula
O'Callaghan et al., U.S. Pat. No. 3,830,700 (8/74), disclose certain 3-arylvinvyl cephalosporins useful as chromogenic agents for the detection of .beta.-lactamase activity. The compounds useful in the patented method were prepared by reacting a 3-phosphoranylidene cephalosporin with a hydrogencarbonyl aryl (aryl aldehyde) compound or by reacting a 3-hydrogencarbonyl cephalosporin with a phosporane of the formula (R)3P=CHAr.
Beeby, U.S. Pat. Nos. 3,983,113 (9/76), 4,049,806 (9/77), and 4,139,618 (2/79) disclose 3-(heterocyclothio)propenyl cephalosporins represented by the formula ##STR3## wherein the compounds were prepared by reacting the starting 3-formyl cephalosporin with a suitable vinyl Grignard reagent to obtain a mixture of .alpha.- and .beta.-hydroxy isomers of the corresponding 3-(1-hydroxyprop-2-enyl) cephalosporin followed by treating the foregoing intermediate with a mercapto substituted heterocycle corresponding to the SR1 substituent in the presence of a small amount of strong acid. Beeby, U.S. Pat. No. 4,112,087 (9/78) discloses compound having the formula shown above except that "OR" is substituted for "S-R.sup.1 "
Webber, U.S. Pat. No. 4,065,620 (12/77) discloses 3-(substituted) vinyl cephalosporins prepared by reacting a 3-formyl cephalosporin compound with a phosphorane of the formula R.sub.1 R.sub.2 R.sub.3 P=CH-Y under conventional Wittig reaction conditions.
Takaya et al., EP App. Publn. 0,030,630 (6/81) disclose 7-acylamino-3-vinylcephalosporanic acid derivatives prepared by reacting a 3-formyl cephalosporin compound with a suitable phosphorane.
Miyadera et al., U.S. Pat. No. 4,147,863 (4/79) disclose cephalosporin derivatives having a (1-alkyl-1H-tetrazol5-yl)vinyl group at the 3-position of the cephem nucleus. The patent discloses preparation of the intermediate having the given 3-vinyl substituent by reacting a known 3-formyl cephalosporin with a Wittig reagent (phosphorane).
Beattie et al., U.S. Pat. No. 4,255,423 (3/81) disclose cephalosporin compounds having a substituted or unsubstituted vinyl group at the 3-position of the cephalosporin nucleus prepared by the reaction of a phosphoranylidene compound with a compound containing a carbonyl group. More particularly, a phosphoranylidene compound of the formula ##STR4## may be reacted with a carbonyl compound of the formula R.sub.2 -CO-R.sub.3 to obtain the -CH=CR.sub.2 R.sub.3 substituent at the 3-position of the cephem nucelus.
It is known in the art to which this invention and the compounds thereby produced relate that the compounds having the cis(Z)-stereoisomeric configuration are preferred over the compounds having the trans(E)-stereoisomeric configuration because the former compounds possess greater antibacterial activity,. (See U.S. Pat. No. 4,520,022, col. 16, lines 23-29).
The processes heretofore known and reported in the literature for producing 3-(1-propenyl)-3-cephems afford a mixture of the cis(Z)- and trans(E)-isomers which requires costly separation to obtain the preferred, more antibacterially active cis(Z)-isomer and, accordingly, the overall yield of desired cis(Z)-isomer based o starting material is relatively low.
Scott, Crisp and Stille, J. Amer. Chem. Soc., 106, 4630(1984) described the palladium-catalyzed coupling of organotins with electrophiles facilitated by the addition of zinc chloride.
Scott and Stille, J. Amer. Chem. Soc., 108, 3033(1986) described the palladium-catalyzed coupling reaction of several vinyl triflates with organostannanes such as, for example, vinyltributylstannane to yield a product having the vinyl group bonded to the carbon atom which has been vacated by the triflate group.
In view of the desirability to improve the processes to produce 3-vinylcephem derivatives having the preferred cis(Z)-stereoisomeric configuration, it has been conceived to apply a stereospecific synthetic route for constructing the Z-propenyl side chain at C(3) of the cephem nucleus utilizing the palladium-catalyzed coupling of a suitably functionalized cephem with cis(Z)-propenyltributylstannane.
Starting with the readily available 3-hydroxycephems and derivatives thereof, including the trifluoromethylsulfonate (triflate) and methanesulfonate and chloro and diphenylphosphate derivates, coupling with the above-mentioned organometallic agents was explored. It was found that the above coupling reactions were unsatisfactory when carried-out according to conditions reported by Scott and Stille (loc. cit.). The coupling between diphenylmethyl 7-(phenylacetamido)-3-triflyloxy-3-cephem-4-carboxylate and stannanes was unsatisfactory when carried out under literature conditions. The use of Pd((C.sub.6 H.sub.5).sub.3 P).sub.4 -LiCl in THF led largely to the 3-chloro derivative of the above-mentioned cephem, which readily isomerized to the .DELTA..sup.2 -cephem while giving only trace amounts of the desired cephem. Use of ZnCl.sub.2 in place of LiCl did not yield any of the .DELTA..sup.2 -cephem by-product. However, conversion to the desired product was so slow when carried out in refluxing THF that extensive decomposition of the starting triflate took place. Consequently the desired product, diphenylmethyl 7-(phenyl- acetamido)-3-(Z-1-propenyl)-3-cephem-4-carboxylate, was obtained only in very poor yield.
SUMMARY OF THE INVENTION
It has been discovered that coupling between 3-triflyloxycephems and certain unsaturated hydrocarbylstannanes (unsaturated hydrocarbyltrialkyl stannanes) can be induced to form a carbon-carbon bond at the 3-position of the cephem nucleus in satisfactory yield and, in the case of the 1-alkenyl and 1-polyalkenyl derivatives, with substantially complete stereospecificity (i.e., greater than 99% stereospeciicity). This is accomplished by carrying out the coupling reaction at room temperature in the presence of a relatively polar aprotic solvent, a Pdo or a PdII compound, certain metal halides, and a phosphine.